Anatomy of the Mesocorticolimbic System

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DA neurons project to various brain regions, including the dorsal and ventral striatum, medial prefrontal cortex, amygdala, and hippocampus (24). The mesocorticolimbic DA system, originating in the ventral tegmental area, consists of numerous topographically organized positive and negative feedback circuits (Fig. 1). As our understanding of the organization of these projections has advanced, new insights have emerged as to the neuronal circuitry mediating the acute actions of psychostimulants as well as the sensitized behavioral responses that occur following their repeated administration. The vast majority of the ventral tegmental area (VTA) projections to the NAc are DAergic (24), whereas about 60% of mesoprefrontal projections contain GABA (25). However, prefrontal cortex (PFC) glutamatergic terminals selectively synapse onto GABA cells that project to the NAc and DA cells that project to the PFC (26). These PFC projections exert an excitatory influence on target cells (27-29). There are data indicating the existence of a direct excitatory PFC drive on mesoaccumbens DA neurons (30,31), but recent data indicate that this drive is mediated by indirect glutamatergic projections to the VTA (26). Alterations in the activity of this PFC-VTA projection may be one mechanism leading to the induction of behavioral sensitization. White et al. (32) have hypothesized that, during repeated treatment with cocaine, DA-induced inhibition of mPFC excitatory amino acid neurons projecting to the VTA diminishes, leading to greater activation of glutamatergic receptors on VTA DA neurons and the induction of cocaine-induced sensitization. Moreover, it has been shown that abstinence from repeated cocaine administration is associated with a decrease in the mPFC DA response to a subsequent cocaine challenge (33,34). This decrease, by increasing the glutamatergic drive on mesoaccumbens DA neurons, may underlie the increase in cocaine-evoked DA release in the NAc that occurs following repeated cocaine (20; Chefer and Shippenberg, in press) or amphetamine

(35) administration and has been implicated in the long-term expression of sensitization.

The majority (up to 90%) of neurons comprising the NAc are medium spiny neurons, containing GABA as the primary neurotransmitter and a variety of neuropep-tides, including neurotensin, enkephalin, dynorphin, substance P, and neurokinin B

(36). The local circuit neurons, which make up approximately 10% of all accumbal cells, contain ether acetylcholine or GABA as well as neuropeptides such as cholecys-tokinin, neurotensin and neuropeptide Y.

The primary excitatory input to the NAc derives from glutamatergic axons of cortical and thalamic origins (37) (Fig. 1). Other excitatory inputs arise from the amygdala

Fig. 1. A schematic drawing of the mesocorticolimbic DA system showing basic organization of the neuronal circuitry and receptor localization in naive and cocaine pretreated animals.

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Fig. 1. A schematic drawing of the mesocorticolimbic DA system showing basic organization of the neuronal circuitry and receptor localization in naive and cocaine pretreated animals.

o co and hippocampus (36,37). DA terminals from the VTA form symmetrical synapses onto dendrites and perikarya of both medium spiny neurons and local circuit neurons. There are distinct differences in innervation of the core and the shell of the NAc (36,38) that underlie the functional differences that exist between these two regions. However, this issue is beyond the topic of the present review.

The basic organization of the NAc described above is far from complete, but serves to provide a rudimentary understanding of the functioning of accumbal neuronal network. DA and glutamate from extrinsic sources and acetylcholine and GABA from local interneurons or collaterals of medium spiny neurons converge on the medium spiny neurons and influence their activity. DA terminals are always found in close proximity to those containing glutamate, and therefore can effectively "gate" signals from cortical areas (36,39-41). Moreover, DA can modulate the response of NAc medium spiny neurons to corticoaccumbens fiber stimulation via D2 receptors, located presynaptically on cortical terminals (42). In addition, the corticoacumbens system is also subject to gating influences by other afferents to the NAc as well. The overlapping inputs from the amygdala and hippocampus appear to be capable of gating PFC information via modulation of NAc neuronal activity (43). Thus, taking into consideration the above observations, one can suggest that the complex neural network of topographically organized positive and negative feedback circuits in the NAc can be modified by various alterations in neurotransmission that occur within the limbic system.

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